How Modafinil Works - The Elusive Mechanism Of Action Of Modafinil

Modafinil’s Mechanism of Action (MOA)

Tentative evidence suggests that modafinil improves cognitive function and mood in healthy subjects. Modafinil has been reported to enhance cognitive performance in schizophrenic patients as an adjunct to antipsychotic medication [^modafinil1], in healthy sleep-deprived [^modafinil2] and non-deprived subjects alike [^modafinil3], and improves executive function in alcohol-dependent patients by modulating the functional connectivity of the default mode network [^modafinil4].

(The default mode network (DMN) is comprised by the brain structures maximally active at rest, and the functional connectivity of this network is classically disrupted in chronic alcoholism.[^modafinil5])

Recent evidence that modafinil enhances vigilance, working memory, impulse control, sustained attention and other cognitive parameters in healthy controls has also emerged [^modafinil6] [^modafinil7] [^modafinil8], though the degree of improvement is likely related to baseline intelligence such that no benefits are observed in the most intelligent cohort.

Safety and Dosage

Modafinil is a widely-prescribed wakefulness promoting agent that is generally safe and well-tolerated at prescribed dosages. However, the theoretical possibility of tipping the balance toward excitotoxicity exists, since modafinil enhances extracellular glutamate release in hypothalamic regions [^modafinil9] with concomitant decrements in gamma-amino-butyric acid (the most ubiquitous inhibitory neurotransmitter in the CNS).

This two-pronged effect whereby excitatory signaling is enhanced and gabaeric signaling is suppressed raises questions about the potential neurotoxicity of modafinil in combination with other allosteric modulators of glutamate receptors, such as the racetams.

Contrary to this line of thinking, it has also been reported that modafinil exhibits antioxidant and neuroprotective properties, while also increasing the cortical phosphocreatine pool.[^modafinil10]. (Phosphocreatine is an even higher energy compound than ATP, and can therefore phosphorylate ADP to restore cytoplasmic ATP when energy reserves are depleted. Impairments in creatine uptake in the brain can cause profound intellectual disability, indication that phosphocreatine is required for normal neuronal bioenergetics. )

The usual dose of modafinil for narcolepsy, obstructive sleep apnea and shift work sleep disorder is 200mg once daily. Physicians also occasionally prescribe modafinil for ADHD, as an alternative to traditional psychostimulants like Adderall or Ritalin.

Modafinil possess novel pharmacodynamic properties. Unlike traditional psychostimulants, modafinil has weak self-reinforcing properties and limited abuse potential, exhibits a much weaker affinity for the dopamine transporter (DAT), and does not ameliorate cataplexy in narcolepsy. These phenomenological differences between modafinil and amphetamines, however, do not exclude the possibility that modafinil’s wake-promoting action are catecholaminergic in nature.

The discovery of modafinil was not driven by rational drug design: rather, it’s mechanism of action has only come under scrutiny after its clinical usefulness was appreciated through empirical observation.

Modafinil and Dopaminergic Signaling

A study in 1994 first revealed that modafinil binds to the dopamine transporter (DAT), albeit with low affinity.[^modafinil11] PET studies in vivo have also demonstrated that modafinil displaces the DA ligand raclopride and cocaine in the human brain.[^modafinil12] Surprisingly (given Modafinil’s relatively weak affinity for the dopamine transporter), the wake-promoting effects of modafinil are completely abolished in mice genetically engineered to lack DAT [^modafinil13].

Moreover, both D1 and D2 antagonists are sufficient to prevent the wakefulness enhancing effects of modafinil in wild-type mice. However, since any modulation of global arousal networks (either excitatory or inhibitory) are likely to affect sensitivity to both stimulants and somnogens (sleep-promoting substances), the effects of manipulating the dopaminergic system on modafinil sensitivity does not unambiguously imply that modafinil’s wake promoting action must be dopaminergic. For example, the dopamine reuptake inhibitor (DRI) methylphenidate reduces sensitivity to anesthetics, but this does not necessarily imply that the mechanism of action of anesthetics involves dopaminergic neurotransmission.

Modafinil and Glutamatergic Signaling

A microdialysis study in rats concluded that modafinil inhibits striatal and pallidal GABA release [^modafinil14]. Moreover, modafinil dose-dependently increases extracellular glutamate and enhances excitatory glutamatergic neurotransmission in the ventromedial (VMT), ventrolateral (VLT), thalamus and hippocampal regions of wild-type rats [^modafinil15]. Hence, modafinil’s tendency to increase the glutamate/GABA ratio may account for some of its wake-promoting effects, although dopamine agonists and dopamine itself both elicit glutamate release in the hippocampus [^modafinil16], raising the possibility that increases in extracellular glutamate may arise secondarily from modafinil’s action on DA.

Orexin/Hypocretin and Histamine Systems

The orexinergic system plays an important role in homeostatic sleep/wake regulation and circadian rhythm. The pathophysiology of narcolepsy involves the autoimmune destruction of orexingeric neurons, highlighting orexin’s role in wake maintenance. Lesioning or ablation of orexinergic neurons in animals models produces a hypersomnolent phenotype. Likewise, histamine is an endogenous wake-promoting amine and therefore histamine blockade (e.g., diphenhydramine) often results in sedation.

It has previously been reported that the intraperitoneal injection of modafinil increases hypothalamic histamine release in freely moving and urethane-anesthetized mice. Moreover, the mechanism of action of modafinil likely also involves orexinergic signaling. Modafinil treatment has been reported to induce c-Fos expression in orexinergic neurons in the perifornical regions of the hypothalamus and in the lateral hypothalamus [^modafinil17] [^modafinil18].

Central injections of orexin peptides elicit histamine release and thus orexin regulates wakefulness via the histaminergic system. Therefore, it has been proposed that modafinil activates the histaminergic system secondarily to its effect on orexinergic inputs.

In summary, modafinil affects a wide array of neurotransmitter systems including catecholamines (dopamine, norepinephrine), glutamate/GABA, as well as histamine and orexin/hypocretin. Modafinil’s mechanism of action likely converges on the hypothalamus, which plays a well-characterized role in sleep regulation and circadian rhythm.